1. Field of the Invention
The invention relates to the technical field of the chemical synthesis of biologically active compounds, preferably for intermediates for the synthesis of fine chemicals and active ingredients from pharmacy and/or agriculture.
2. Description of Related Art
In principle, the selective exchange of hydrogen on an aromatic system with a substituted carbon atom belongs to one of the fundamental reactions in organic chemistry and is therefore known.
One class of compounds which can be prepared in this way is, for example, optionally substituted 3-alkylthioindol-2-ones (3-(alkylsulfanyl)-1,3-dihydro-2H-indol-2-ones), which can in turn be converted to optionally substituted 2-oxindoles (1,3-dihydro-2H-indol-2-ones). Optionally substituted oxindoles and their precursors, such as optionally substituted 3-alkylthioindol-2-ones, are versatile intermediates for active ingredient syntheses (Bioorg. Med. Chem. Lett. 2006, 16, 2109; JP 2008-101014; WO 96/41799 A1). Further uses as precursors to pharmaceutical compounds are described in: US 2005/0090541 A1, EP 636608 A, U.S. Pat. No. 4,690,943A.
Most of the described various syntheses of oxindoles use a variation of a Friedel-Crafts reaction (Stolle Synthesis, W. C. Sumpter, Chem. Rev. 1945, 37, 443-449). However, Stolle syntheses can only be used with restrictions since they require strongly acidic conditions and an electron-rich aniline. In addition, however, radical, nitrenium ion and organolithium reactions, and also photochemically dependent methods are also known. However, these are also limited by the type of oxindoles to be prepared, the compatibility of substrates, the reaction conditions, and also by the fact that the aromatic must already have a halogen substituent which is then replaced. (Radical processes: Zard et al., Tetrahedron Lett. 1994, 35, 9553-9556; Zard et al., Tetrahedron Lett. 1994, 35, 1719-1722; Jones et al., Tetrahedron Lett. 1994, 35, 7673-7676; Kikugawa et al., Chem. Letters 1987, 1771-1774; Clark et al., Synthesis 1991, 871-878; Yonemitsu et. al., Chem. Pharm. Bull. 1981, 29, 128-136; see scheme 1).

The process by Gassman et al. (Organic Synthesis Coll., vol. 6, 601 and vol. 56, 72), which proceeds from aniline and methyl thioacetate ester via chlorination and treatment with triethylamine at −70° C., appears suitable with regard to feasibility, availability of starting materials, short reaction rate and reproducibility. However, it is also described that good yields can only be achieved if the unstable N-chloro (1) or N-sulfonium (2) intermediates are formed below −65° C., in the normal case at −78° C. (Gassman et. al., J. Am. Chem. Soc., 1974, 96(17), 5508; Gassman et al., J. Am. Chem. Soc., 1974, 96(17), 5512; WO 96/41799 A1; see scheme 2).

The chlorinating agent of choice according to the literature is the unstable and explosive tert-butyl hypochlorite since the by-product of the chlorination then gives the neutral tert-butyl alcohol. In the few cases in which sulfuryl chloride (SO2Cl2) has been used, a second, non-nucleophilic base, such as “proton sponge”, has been used (Johnson, J. Org. Chem. 1990, 55, 1374; Warpehoski, Tetrahedron Lett. 1986, 27, 4103). Since both variants are carried out at low temperatures, however, this is not a practicable solution on an industrial scale.
Wright et al. (Tetrahedron Lett. 1996, 37, 4631) describe an alternative where the chlorosulfonium intermediate (3) has been prepared from a sulfoxide and oxalyl chloride (see scheme 3). Here, the chlorosulfonium intermediate (3) is likewise unstable. For this reaction, the sulfoxide must first be prepared and isolated. For reasons of stability, the reaction must proceed at −78° C. and, in order to avoid a reaction between aniline and oxalyl chloride, the reaction is carried out in stages.

The compounds (4) described by this process (scheme 2 or scheme 3) can only be prepared because of the mechanism of the reaction via the compounds (2). Inevitably here, the use of a base (C) is required for the rearrangement to the compounds (4). In the literature, an additional base to the aniline (compounds of formula Q) such as “proton sponge” or triethylamine is specified for this purpose. The additional base used in these processes must inevitably be recovered in the case of syntheses on an industrial scale and be separated from the unreacted compounds of formula Q in order to be able to use the reisolated compounds of formula Q again as starting materials.
The reasons why the reaction is so sensitive to reaction temperatures above −70° C. and why it has always been carried out in stages are manifold.
Firstly, the functional groups which participate in the reaction, i.e. the nitrogen atom of the aniline and the sulfur atom of the thioether, occur unchanged both in the product (4) and also in the starting material. Consequently, a selective chlorination during the reaction would not be expected in which the product (4) is formed directly. For this reason, all methods known in the literature use a stepwise reaction.
Moreover, at temperatures higher than −65° C., the N-chloroaniline is able to convert to an aromatic chlorinated in the ring, and also form other oxidation products (dimers). It is therefore not surprising that the acetanilide which is significantly less electron-rich and thus significantly less chlorination-reactive to the ring only forms ring chlorinations with tert-butyl hypochlorite at 0° C. (Lengyel et. al. Synth. Comm., 1998, 28 (10), 1891-1896).
Furthermore, the sulfonium intermediates (2) or (3) can eliminate in the presence of bases and form the reactive by-product (5), which would condense, e.g. with an aniline, as a result of which the secondary component (6) is produced irreversibly (see scheme 4). This corresponds to the so-called Pummerer oxidation of the R2-CH—R3 radical.

It was therefore the object to provide a modified process which permits a preparation, improved compared to the aforementioned processes, of compounds (4) via intermediates (2) (sulfonium salts) on an industrial scale with advantages such as improved overall yield and/or product purity, reduced use of starting materials, omission of further auxiliaries (such as, e.g. a second base) or simplified process course (such as, e.g. reactions at a higher temperature) or use of industrially more suitable solvents (less toxic, better recoverable).
The compounds (4) prepared in this way should preferably also permit further processing to oxindoles (1,3-dihydro-2H-indol-2-ones), which may likewise be intermediates for the synthesis of fine chemicals and active ingredients from pharmacy and/or agriculture.